1-(acetylaminophenyl)-2-aminopropanone derivatives and central nervous system antidepressant compositions

ABSTRACT

The present invention relates, by way of new industrial products, to 1-(acetylaminophenyl)-2-amino-propanone derivatives selected from the group consisting of 
     (a) the compounds of the formula 
     
         Ar--CO--CH(CH.sub.3)--NR.sub.1 R.sub.2                     (I) 
    
      in which 
     R 1  represents a C 1  -C 4  alkyl group or a C 3  -C 6  cycloalkyl group; 
     R 2  represents the hydrogen atom or a C 1  -C 4  alkyl group; 
     R 1  and R 2 , taken together, can form, with the nitrogen atom to which they are bonded, an N-heterocyclic group with 5 to 7 ring members, capable (i) of including a second heteroatom selected from N, O and S, and (ii) of being substituted, the said heterocyclic group NR 1  R 2  being selected from the group comprising pyrrolidino, morpholino, thiomorpholino, piperidino, hexamethyleneimino, piperazino, 4-methylpiperazino, 4-(β-hydroxyethyl) piperazino, 4-phenylpiperazino and 4-(p-chlorophenyl)-piperazino groups; and 
     Ar represents an acetylaminophenyl group of the formula ##STR1##  in which X is CH 3  CONH and Y and Z, which can be identical or different, each represent a hydrogen or halogen atom; and 
     (b) their addition salts. 
     These new products are useful in therapy. 
     The invention also relates to the method for their preparation.

This application is a divisional of U.S. Ser. No. 038,981 filed Apr. 16,1987, now U.S. Pat. No. 4,877,812, which is a continuation-in-partapplication of U.S. Ser. No. 660,285 filed Oct. 12, 1984, now abandoned.

FIELD OF THE INVENTION

The present invention relates to new1-(acetyl-aminophenyl)-2-aminopropanone derivatives. It also relatesfirstly to the use of these new derivatives in therapy, especially asantidepressants for the central nervous system (CNS), and secondly tothe method for their preparation.

PRIOR ART

U.S. Pat. No. 3,644,520 (HARTLEY et al.) discloses the use of1-(3-acetylaminomethyl-4-hydroxyphenyl)-2-aminopropanones asintermediate compounds in the synthesis of1-(3-acetylaminomethyl-4-hydroxyphenyl)-2-aminopropanol compounds.

U.S. Pat. No. 2,393,820 (SCHNIDER) discloses the use of1-(3-acetylamino-4-hydroxyphenyl)-2-(N-methylamino)-ethanones asintermediate compounds in the synthesis of corresponding1-(3-acetylamino-4-hydroxyphenyl)-2-(N-methylamino)ethanol products.

U.S. Pat. No. 3,488,737 (GORDON) relates to antibacterial aminoacidderivatives wherein the terminal N atom of the aminoacid moiety issubstituted by a (CH₃ CONHC₆ H₅) COCH₂ CH₂ radical.

Some N-(acetylaminophenyl-alkylene)amines were provided or suggested assympathomimetic and CNS-stimulant agents--see U.S. Pat. No. 4,015,011(SCHROMM et al.)--or an anorexic, anti-hallucinogenic, anti-Parkinsonand anti-inflammatory agents--see U.S. Pat. No. 3,729,475 (WILLIAMSON etal.)-.

OBJECT OF THE INVENTION

This invention is concerned with new1-(acetylaminophenyl)-2-aminopropanone derivatives which arestructurally different from the prior art compound and are useful aspharmaceuticals. These new derivatives all act of the CNS, in particularas antidepressants. In addition to the antidepressant properties commonto this group of derivatives, it is found that these derivatives havestimulant (or excitant) effects on the CNS. Furthermore, some of thesederivatives possess beneficial immunological and/or cardiovasculareffects as indicated below.

DETAILED DISCLOSURE OF THE INVENTION

The new 1-(acetylaminophenyl)-2-aminopropanone derivatives recommendedhere are selected from the group consisting of

(a) the compounds of the formula

    Ar--CO--CH(CH.sub.3)--NR.sub.1 R.sub.2                     (I)

in which

R₁ represents a C₁ -C₄ alkyl group or a C₃ -C₆ cycloalkyl group;

R₂ represents the hydrogen atom or a C₁ -C₄ alkyl group;

R₁ and R₂, taken together, can form, with the nitrogen atom to whichthey are bonded, an N-heterocyclic group with 5 to 7 ring members,capable (i) of including a second heteroatom selected from the groupcomprising N, O and S, and (ii) of being substituted, the saidheterocyclic group NR₁ R₂ being selected from the group consisting ofpyrrolidino, morpholino, thiomorpholino, piperidino, hexamethyleneimino,piperazino, 4-methylpiperazino, 4-(β-hydroxyethyl)piperazino,4-phenylpiperazino and 4-(p-chlorophenyl)piperazino groups; and

Ar represents an acetylaminophenyl group of the formula ##STR2## inwhich X is CH₃ CONH and Y and Z, which can be identical or different,each represent a hydrogen or halogen atom; and

(b) their addition salts.

The groups CH₃, CH₂ CH₃, CH₂ CH₂ CH₃, CH(CH₃)₂, C(CH₃)₃, CH(CH₃)CH₂ CH₃,CH₂ CH(CH₃)₂ and CH₂ CH₂ CH₂ CH₃ may be mentioned in particular amongthe C₁ -C₆ alkyl groups included in the definitions of the groups R₁ andR₂.

The cyclopropyl, cyclopentyl and cyclohexyl groups may be mentioned inparticular among the C₃ -C₆ cycloalkyl groups included in the definitionof the group R₁.

The N-heterocyclic groups NR₁ R₂ suitable according to the invention areadvantageously saturated. They comprise from 5 to 7 ring members, caninclude a second heteroatom selected from the group consisting of N, Oand S and can be substituted especially by C₁ -C₄ alkyl groups, C₁ -C₄hydroxyalkyl groups (especially CH₂ CH₂ OH) or aryl or halogenoarylgroups (especially phenyl and 4-chlorophenyl).

F, Cl and Br may be mentioned as particularly suitable among the halogenatoms included in the definitions of the groups Y and Z, the preferredhalogen atom here being Cl. The acetylamino group X=CH₃ CONH can be inthe ortho, meta or para position, the meta and para positions beingpreferred. The preferred groups Ar are 4-acetylaminophenyl,4-acetylamino-3-chlorophenyl, 4-acetylamino-3,5-dichlorophenyl,3-acetylaminophenyl and 3-acetylamino-4-chlorophenyl groups.

The expression "addition salts" is understood here as meaning firstlythe acid addition salts obtained by reacting one of the abovementionedfree bases with an inorganic or organic acid, and secondly the ammoniumsalts, Hydrochloric, hydrobromic, acetic, formic, propionic, oxalic,fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic,tartaric, aspartic, glutamic, methanesulfonic and p-toluenesulfonicacids may be mentioned in particular among the acids which can be usedto salify the abovementioned free bases. CH₃ I and CH₃ Cl may bementioned in particular among the compounds making it possible to obtainammonium salts. In general terms, the acid addition salts are preferredto the ammonium salts.

A number of compounds according to the invention have been collated inTable I below without in any way implying a limitation. The meltingpoints given are instantaneous melting points determined on a Koflerbench.

                                      TABLE I                                     __________________________________________________________________________     ##STR3##                                                                                                           Melting point                           Product Code No.                                                                             X      Y  Z  NR.sub.1 R.sub.2                                                                        (°C.)                            __________________________________________________________________________    Example 1 (a)                                                                         CRL 41 152                                                                           4-CH.sub.3 CONH                                                                      H  H  NHCH(CH.sub.3).sub.2                                                                    240                                     Example 2 (a)                                                                         CRL 41 177                                                                           4-CH.sub.3 CONH                                                                      H  H  NHC(CH.sub.3).sub.3                                                                     (b)                                     Example 3 (a)                                                                         CRL 41 192                                                                           4-CH.sub.3 CONH                                                                      3-Cl                                                                             H  NHCH(CH.sub.3).sub.2                                                                    260                                     Example 4 (a)                                                                         CRL 41 212                                                                           4-CH.sub.3 CONH                                                                      H  H  NH(CH.sub.2).sub.2 CH.sub.3                                                             230 (c)                                 Example 5 (a)                                                                         CRL 41 217                                                                           4-CH.sub.3 CONH                                                                      H  H  NHCH.sub.3                                                                              (d)                                     Example 6 (a)                                                                         CRL 41 219                                                                           4-CH.sub.3 CONH                                                                      3-Cl                                                                             H  pyrrolidino                                                                             260                                     Example 7 (a)                                                                         CRL 41 220                                                                           4-CH.sub.3 CONH                                                                      3-Cl                                                                             5-Cl                                                                             NHCH(CH.sub.3).sub.2                                                                    (b)                                     Example 8 (a)                                                                         CRL 41 224                                                                           4-CH.sub.3 CONH                                                                      H  H  NHCH.sub.2 CH.sub.3                                                                     230 (c)                                 Example 9 (a)                                                                         CRL 41 232                                                                           4-CH.sub.3 CONH                                                                      H  H  N(CH.sub.3).sub.2                                                                       252 (c)                                 Example 10 (a)                                                                        CRL 41 236                                                                           4-CH.sub.3 CONH                                                                      H  H  morpholino                                                                              255 (c)                                 Example 11 (a)                                                                        CRL 41 240                                                                           4-CH.sub.3 CONH                                                                      H  H  piperidino                                                                              240 (c)                                 Example 12 (e)                                                                        CRL 41 242                                                                           4-CH.sub.3 CONH                                                                      H  H                                                                                 ##STR4## 230 (c)                                 Example 13 (a)                                                                        CRL 41 245                                                                           4-CH.sub.3 CONH                                                                      H  H                                                                                 ##STR5## 200 (c)                                 Example 14 (a)                                                                        CRL 41 247                                                                           4-CH.sub.3 CONH                                                                      H  H                                                                                 ##STR6## 200-210 (c)                             Example 15 (a)                                                                        CRL 41 254                                                                           3-CH.sub.3 CONH                                                                      H  H  NHCH(CH.sub.3).sub.2                                                                    250 (c)                                 Example 16 (a)                                                                        CRL 41 259                                                                           3-CH.sub.3 CONH                                                                      H  H  N(CH.sub.3).sub.2                                                                       250 (c)                                 Example 17 (a)                                                                        CRL 41 262                                                                           3-CH.sub.3 CONH                                                                      H  H                                                                                 ##STR7## 245 (c)                                 Example 18 (a)                                                                        CRL 41 267                                                                           3-CH.sub.3 CONH                                                                      H  H                                                                                 ##STR8## 220 (c)                                 Example 19 (a)                                                                        CRL 41 269                                                                           3-CH.sub.3 CONH                                                                      H  H                                                                                 ##STR9## 250                                     Example 20 (a)                                                                        CRL 41 277                                                                           3-CH.sub.3 CONH                                                                      H  H  NH(CH.sub.2).sub.2 CH.sub.3                                                             220 (c)                                 __________________________________________________________________________     Notes                                                                         (a): hydrochloride;                                                           (b): the melting point is above 260° C.;                               (c): with decomposition;                                                      (d): the melting point is above 250° C.;                               (e): dihydrochloride.                                                    

The new 1-(acetylaminophenyl)-2-aminopropanone derivatives can beprepared in accordance with a method known per se, by the application ofclassical reaction mechanisms. Two methods of synthesis, representeddiagrammatically by the following reactions, are recommended for thepreparation of these derivatives: ##STR10##

Variant A consists in reacting a halogen derivative of the formula III(in which Ar is defined as indicated above and Hal represents a halogenatom, in particular Cl or Br and preferably Cl for the yield) with anamine of the formula IV (in which R₁ and R₂ are defined as indicatedabove).

Preferably, more than one mol of IV will be used per mol of III, theamine IV participating simultaneously as a reactant and as a solvent orco-solvent for the reaction. The said reaction of the1-(acetylaminophenyl)-2-halogenopropanone III with the amine IV isadvantageously carried out, according to Variant A, for at least 0.5hour, at a temperature of between 15° C. and the reflux temperature ofthe reaction medium.

Variant B consists in subjecting a 1-(aminophenyl)-2-aminopropanonederivative of the formula V (in which Y, Z, R₁ and R₂ are defined asindicated above) to an acetylation reaction by means of an acetylatingagent which is in excess relative to the stoichiometric conditions andwhich is selected from the group consisting of acetyl halides(preferably CH₃ COCl for the yield) and acetic anhydride, (CH₃ CO)₂ O.The compounds of the formula V are described in published French patentapplication FR-A-2 569 184 (filed on Aug. 20, 1984) of the Applicant.

According to Variant B, the derivative of the formula V willadvantageously be reacted in CH₃ COCl, for at least 2 hours, at thereflux temperature of the reaction medium, in a proportion of at least 2mol of CH₃ COCl (preferably 3 to 5 mol of CH₃ COCl) per mol of V.

In general, it is preferred to use Variant A rather than Variant B forthe synthesis of all the 1-(acetylaminophenyl)-2-aminopropanonederivatives. In practice, Variant B is only used for the compounds inwhich Y=Z=halogen.

The present 1-(acetylaminophenyl)-2-aminopropanone derivatives areuseful in therapy. They all act on the CNS, more precisely asantidepressants. They have a stimulant or excitant component in theirneuropsychopharmacological profile. In addition to these effects on theCNS, some of these derivatives also have valuable immunologicalproperties; in particular, the products of Examples 7 (CRL 41 220), 12(CRL 41 242), 14 (CRL 41 247), 15 (CRL 41 254) and 17 (CRL 41 262) havebeneficial immunomodulating effects in the treatment of patients havingan insufficient immunoreaction, the most valuable products in respect oftheir immunological properties being the products of Examples 7 (CRL 41220), 12 (CRL 41 242) and 17 (CRL 41 262).

The best mode for carrying out this invention consists in using, aspreferred CNS-active agents, the products of Examples 1 (CRL 41 152, themost preferred compound), 2 (CRL 41 177), 3 (CRL 41 192), 6 (CRL 41219), 7 (CRL 41 220) and 8 (CRL 41 224).

According to the invention, a therapeutic composition is recommendedwhich contains, in association with a physiologically acceptableexcipient, at least one 1-(acetylaminophenyl)-2-aminopropanonederivative or one of its non-toxic addition salts as the activeprinciple.

Of course, in a composition of this type, the active principle ispresent in a pharmaceutically effective quantity.

Further advantages and characteristics of the invention will beunderstood more clearly on reading the following description ofpreparative examples on the one hand and results of pharmacologicaltests on the other; these data as a whole do not imply a limitation butare given by way of illustration.

PREPARATION I Preparation of1-(4-acetylamino-3,5-dichlorophenyl)-2-isopropylaminopropanonehydrochloride ##STR11##

28 g of 1-(4-aminophenyl)-2-isopropylaminopropanone are dissolved in 100ml of distilled water. This solution The mixture is stirred for 2 hoursand then evaporated to dryness in vacuo. The evaporation residue, whichis a brown solid, is taken up in acetic acid and, on recrystallization,gives 11 g (yield: 35%) of1-(4-amino-3,5-dichlorophenyl)-2-isopropylaminopropanonedihydrochloride.

Melting point (inst.)>260° C.

A mixture of the 11 g of the product thus obtained with 50 ml of CH₃COCl is heated under reflux for 4 hours. The excess acetyl chloride isthen evaporated off in vacuo. The evaporation residue is taken up withethanol to give 9 g (yield: 25%) of CRL 41 220.

Melting point (inst.)>260° C.

PREPARATION II Preparation of1-(4-acetylaminophenyl)-2-ethylaminopropanone hydrochloride ##STR12## a/1-(4-Acetylaminophenyl)-2-chloropropanone

92 g (0.72 mol) of 2-chloropropionyl chloride [Cl-CO-CHCl-CH₃ ] are runover a period of 40 minutes into a suspension consisting of 54 g (0.40mol) of acetanilide, 160 g (1.20 mol) of aluminum chloride and 400 ml ofcarbon disulfide. The reaction medium is heated under reflux for 1 hourand then poured into a water/ice mixture acidified with dilutehydrochloric acid, and the mixture is then stirred overnight at ambienttemperature (15°-25° C.). The precipitate formed is collected byfiltration and then purified by recrystallization from benzene to give78 g (yield: 86.5%) of 1-(4-acetylaminophenyl)-2-chloropropanone.

Melting point (inst.)=120° C.

b/ CRL 41 224

A solution of 25 g (0.11 mol) of1-(4-acetylaminophenyl)-2-chloropropanone in 164 ml (1.10 mol) of anaqueous solution of ethylamine containing 330 g/liter is heated at about60°-70° C. for 1 hour. The excess ethylamine is evaporated off underreduced pressure, the evaporation residue is extracted with severalportions of ethyl acetate and the dried ethyl acetate phase is thentreated with a solution of hydrogen chloride in ethanol. The precipitateformed is purified by washing with hot anhydrous ethanol to give 13.3 g(yield of stage b: 44.7%; overall yield: 38.7%) of CRL 41 224.

Melting point (inst.)=230° C. (with decomposition).

PREPARATION III Preparation of1-(4-acetylaminophenyl)-2-piperidinopropanone hydrochloride ##STR13##

A solution consisting of 18 g (0.0798 mol) of1-(4-acetylaminophenyl)-2-chloropropanone, 78.8 ml (0.7980 mol) ofpiperidine and 50 ml of water is stirred for 1 hour at normal ambienttemperature (15°-25° C.) and then for 0.5 hour under reflux. It isevaporated to dryness under reduced pressure and the evaporation residueis taken up with ethyl acetate. The ethyl acetate phase is washed withwater and dried over Na₂ SO₄ and the solvent is evaporated off to give25 g of an orange-brown oil. This oil is treated in ethyl acetate with asolution of hydrogen chloride in ethanol.

Purification by crystallization and treatment with carbon black (CXAblack) in anhydrous ethanol gives 19.8 g (yield: 79.9%) of CRL 41 240.

Melting point (inst.)=240° C. (with decomposition).

PREPARATION IV Preparation of1-(4-acetylaminophenyl)-2-(4-methylpiperazino)propanone dihydrochloride##STR14##

A mixture of 18.5 g (0.082 mol) of1-(4-acetylaminophenyl)-2-chloropropanone and 91 ml (0.820 mol) of4-methylpiperazine in 60 ml of H₂ O is stirred for 1 hour at ambienttemperature and then for 0.5 hour under reflux. The reaction medium istaken up with 100 ml of H₂ O, and 11.6 g of1-(4-acetylaminophenyl)-2-(4-methylpiperazino)propanone are isolated byfiltration.

Melting point (inst.)=90° C.

The free base thus obtained is dissolved in anhydrous ethanol andtreated with carbon black (CXA black) and then with a solution ofhydrogen chloride in ethanol. The precipitate formed is isolated byfiltration to give 14.1 g (yield: 47.5%) of CRL 41 242.

Melting point (inst.)=230° C. (with decomposition).

PREPARATION V Preparation of1-(4-acetylamino-3-chlorophenyl)-2-pyrrolidinopropanone hydrochloride##STR15## a/ 1-(4-Acetylamino-3-chlorophenyl)-2-chloropropanone

45 g (0.199 mol) of 1-(4-acetylaminophenyl)-2-chloropropanone aresuspended in 400 ml of CHCl₃. 0.2 mol of Cl₂ is introduced by bubbling.This gives a yellow solution, which is evaporated to dryness.Recrystallization of the evaporation residue from toluene gives 26 g(yield: 50%) of 1-(4-acetylamino-3-chlorophenyl)-2-chloropropanone.

Melting point (inst.)=118° C.

b/ CRL 41 219

26 g of 1-(4-acetylamino-3-chlorophenyl)-2-chloropropanone are dissolvedin a mixture of 100 ml of pyrrolidine and 20 ml of water. The solutionis heated under reflux for 2 hours and the excess pyrrolidine isevaporated off in vacuo. The oily evaporation residue is taken up in C₂H₅ OH and precipitated by means of HCl gas. This gives 8 g (yield: 24%)of CRL 41 219.

Melting point (inst.)=260° C.

PREPARATION VI Preparation of1-(3-acetylaminophenyl)-2-piperidinopropanone hydrochloride ##STR16## a/1-(3-Acetylaminophenyl)-2-bromopropanone

30.4 g (0.19 mol) of bromine are run over a period of 2.5 hours, atambient temperature, into a solution of 37 g (0.19 mol) of1-(3-acetylaminophenyl)propanone in a mixture of 300 ml oftetrahydrofuran and 300 ml of diethyl ether, in the presence of a traceof AlCl₃. The reaction medium is degassed at about 40° C. by means of astream of nitrogen and evaporated at dryness under reduced pressure. Theevaporation residue is purified by crystallization from ethyl acetate togive 26.5 g (yield: 51.6%) of 1-(3-acetylaminophenyl)-2-bromopropanone.

Melting point (inst.)=133° C.

b/ CRL 41 262

A mixture of 18.5 g (0.0685 mol) of1-(3-acetylaminophenyl)-2-bromopropanone, 68 ml (0.685 mol) ofpiperidine and 45 ml of water is stirred for 1 hour at ambienttemperature. The reaction medium is evaporated to dryness under reducedpressure, the evaporation residue is taken up with ethyl acetate and theinsoluble material is removed by filtration. The filtrate is washed withwater, dried over Na₂ SO₄ and then treated with a solution of hydrogenchloride in ethanol. The precipitate formed is purified byrecrystallization from a C₂ H₅ OH/CH₃ OH mixture (3:5 v/v) to give 15 g(yield: 70.7%) of CRL 41 262.

Melting point (inst.)=245° C. (with decomposition).

PREPARATION VII Preparation of1-(4-acetylaminophenyl)-2-isopropylaminopropanone hydrochloride##STR17##

(a) 1-(4-Acetylaminophenyl)-2-chloropropanone

27 g of acetanilide are introduced into a mixture comprising 67 g ofAlCl₃ and 76.8 g of 2-chloropropionyl chloride [Cl--CO--CHCl--CH₃ ], ata temperature of between 35° and 45° C. The mixture is stirred until allthe acetanilide has dissolved. The reaction medium thus obtained ispoured onto crushed ice; the precipitate formed is collected byfiltration, washed with water until the pH of the washings is 7, anddried to give 39 g (yield: 86%) of1-(4-acetylaminophenyl)-2-chloropropanone.

Melting point (inst.)=124° C.

(b) CRL 41 152

The 39 g of 1-(4-acetylaminophenyl)-2-chloropropanone thus obtained aredissolved in 200 ml of isopropylamine. The resulting reaction medium isheated under reflux for 6 hours. The excess isopropylamine is evaporatedoff in vacuo. The evaporation residue, which is in the form of a viscousoil, is taken up with 200 ml of anhydrous ethanol and the hydrochlorideis precipitated by means of a stream of HCl gas. Recrystallization fromethanol gives 40 g (yield: 70%) of CRL 41 152, which is in the form of avery water-soluble white powder.

Melting point=240° C.

PREPARATION VIII Preparation of1-(4-acetylamino-3-chlorophenyl)-2-isopropylaminopropanone hydrochloride(Example 3; Code No.: CRL 41 192) (a)1-(4-Acetylamino-3-chlorophenyl)-2-chloropropanone

45 g of 1-(4-acetylaminophenyl)-2-chloropropanone are suspended in 400ml of CHCl₃. 0.2 mol of Cl₂ is introduced by bubbling. The resultingyellow solution is evaporated to dryness. Recrystallization of theevaporation residue from toluene gives 26 g (yield: 50%) of1-(4-acetylamino-3-chlorophenyl)-2-chloropropanone.

Melting point (inst.)=118° C.

(b) CRL 41 192

The 26 g of 1-(4-acetylamino-3-chlorophenyl)-2-chloropropanone thusobtained are dissolved in 150 ml of isopropylamine. The solution isheated under reflux for 4 hours and the excess isopropylamine isevaporated off in vacuo. The evaporation residue, which is in the formof an oil, is taken up in ethanol and the hydrochloride is precipitatedby means of a stream of HCl gas.

This gives 9.6 g (yield: 15%) of CRL 41 192.

Melting point=260° C.

The results of the tests which were undertaken with the compoundsaccording to the invention have been summarized below.

A. TESTS RELATING TO CRL 41 224 (PRODUCT OF EXAMPLE 8)

In the neuropsychopharmacological study which follows, CRL 41 224, insolution in distilled water (pH 6), was administered intraperitoneallyin a volume of 20 ml/kg to male mice and 5 ml/kg to male rats.

I. TOXICITY

In male mice, the LD-0 (maximum non-lethal dose) by intraperitonealadministration is greater than 256 mg/kg and less than 512 mg/kg.

II. OVERALL BEHAVIOR AND REACTIVITIES

Groups of three animals are observed before and then 0.25 hour, 0.50hour, 1 hour, 2 hours, 3 hours and 24 hours after the administration ofCRL 41 224. The following observations are made:

1°. in mice

at doses of 2 and 8 mg/kg

forms of behavior, reactivities and variations in the pupil diameter andrectal temperature all substantially comparable to those of the controlgroup receiving only distilled water;

at a dose of 32 mg/kg

excitation for 3 hours,

sterotypies lasting between 2 and 3 hours, and

an increase in the reactivity to touch and muscular tonus for between 2and 3 hours;

at a dose of 128 mg/kg

excitation for 3 hours,

stereotypies lasting between 2 and 3 hours,

an increase in the reactivity to touch and muscular tonus for 24 hours,

hyperthermia for between 2 and 3 hours (+0.9° C.), and

moderate mydriasis for 3 hours;

2°. in rats

at a dose of 1 mg/kg

brief mydriasis appearing 0.5 hour after administration of CRL 41 224;

at a dose of 4 mg/kg

mydriasis lasting 2 hours;

at a dose of 16 mg/kg

stereotypies for 3 hours, and

mydriasis lasting 3 hours;

at a dose of 64 mg/kg

excitation for 1 hour,

stereotypies for 3 hours,

piloerection for 1 hour,

an increase in the reactivity to touch and muscular tonus for 3 hours,

hyperthermia for 3 hours (+1.5° C.), and

mydriasis for 3 hours.

III. INTERACTION WITH APOMORPHINE

1. in mice

Groups of 6 mice receive CRL 41 224 0.5 hour before the subcutaneousinjection of 1 or 16 mg/kg of apomorphine. It is observed that, at dosesof 8 mg/kg, 32 mg/kg and 128 mg/kg, CRL 41 224 opposes the hypothermiainduced by apomorphine, without modifying the righting behavior andstereotypy behavior.

2. in rats

CRL 41 224 is administered to groups of 6 rats 0.5 hour before thesubcutaneous injection of 0.5 mg/kg of apomorphine. It is observed that,at a dose of 16 mg/kg, but especially at a dose of 64 mg/kg, CRL 41 224causes potentiation of the stereotypies induced by apomorphine.

IV. INTERACTION WITH AMPHETAMINE

Amphetamine (2 mg/kg) is injected intraperitoneally into groups of 6rats 30 minutes after the administration of CRL 41 224. It is foundthat, at a dosage of 16 mg/kg, but especially at a dose of 64 mg/kg, CRL41 224 causes potentiation of the stereotypies induced by amphetamine.

V. INTERACTION WITH RESERPINE

Four hours after the intraperitoneal injection of 2.5 mg/kg ofreserpine, groups of 6 mice receive CRL 41 224.

It is noted that, as from a dose of 2 mg/kg, CRL 41 224 opposes thehypothermia induced by reserpine. This antagonism is significant fordoses of 32 mg/kg and 128 mg/kg and, at a dose of 128 mg/kg, CRL 41 224reduces the intensity of the ptosis induced by reserpine.

VI. INTERACTION WITH OXOTREMORINE

CRL 41 224 is administered to groups of 6 mice 0.5 hour before theintraperitoneal injection of 0.5 mg/kg of oxotremorine.

1. Action on the temperature

It is found that, at doses of 2 mg/kg and 8 mg/kg, but especially atdoses of 32 mg/kg and 128 mg/kg, CRL 41 224 opposes the hypothermicaction of oxotremorine.

2. Action on the trembling

It is found that, at doses of 8 mg/kg and 32 mg/kg, but especially 128mg/kg, CRL 41 224 distinctly reduces the intensity of the tremblinginduced by oxotremorine.

3. Action on the peripheral cholinergic symptoms

It is observed that, in practice, CRL 41 224 does not modify the signsof peripheral cholinergic stimulation induced by oxotremorine.

VII. ACTION ON THE FOUR PLATE TEST, TRACTION AND ELECTRIC SHOCK

The test is performed on groups of 10 mice 30 minutes after theadministration of CRL 41 224.

It is found that, at a dose of 128 mg/kg, CRL 41 221 causes an increasein the number of punished passes, does not cause major motor incapacity,does not aggravate the convulsant effects and does not modify the lethaleffects of electric shock.

VIII. ACTION ON THE SPONTANEOUS MOTILITY

0.5 hour after they have received CRL 41 224, the mice (6 per dose, 12control animals) are placed in an actimeter, where their motility isrecorded for 30 minutes.

It is observed that, at a dose of 8 mg/kg and especially at doses of 32mg/kg and 128 mg/kg, CRL 41 224 increases the spontaneous motor activityof the mice.

IX. ACTION ON THE INTERGROUP AGGRESSION

After they have stayed for 3 weeks in the 2 halves of a cage divided byan opaque partition, groups of 3 mice receive CRL 41 224. Half an hourlater, the two groups from the same cage are brought together by removalof the partition, and the number of fights which occur in 10 minutes isnoted. Half the test is performed on ordinary mice (NMRI, C.E.R.January) and half an NMRI (Iffa Credo) mice.

It is found that, at a dose of 128 mg/kg, CRL 41 224 reduces the numberof fights.

X. ACTION TOWARDS SOME FORMS OF BEHAVIOR PERTURBED BY VARIOUS AGENTS

1. Motility reduced by habituation to the enclosure

After they have stayed in the actimeters for 18 hours, the mice (6 perdose, 12 control animals) receive CRL 41 224. They are immediatelyreturned to their respective enclosures and, half an hour later, theirmotility is recorded for 30 minutes.

It is observed that, at doses of 32 mg/kg and 128 mg/kg, CRL 41 224causes a distinct resumption in the motor activity of mice accustomed totheir enclosure.

2. Motility reduced by hypoxic aggression

Half an hour after they have received CRL 41 224, the mice (10 per dose,20 control animals) are subjected to acute hypobaric anoxia [pressurereduction of 600 mm Hg (i.e. about 8×10⁴ Pa) in 90 seconds; release ofvacuum in 45 seconds] and are then placed in an actimeter, where theirmotility is recorded for 10 minutes.

It is observed that, at doses of 8 mg/kg, 32 mg/kg and especially 128mg/kg, CRL 41 224 causes a distinct improvement in the motor recovery inmice whose motility has been depressed following a brief period in areduced-pressure enclosure.

3. Asphyxiant anoxia

Groups of 10 mice receive CRL 41 224 half an hour before theintraperitoneal administration of 32 mg/kg of gallamine triiodoethylate(reference curarizing agent).

It is observed that CRL 41 224 does not change the time taken forconvulsions and death to occur following asphyxiant anoxia caused by acurarizing agent.

XI. INTERACTION WITH BARBITAL

Half an hour after the administration of CRL 41 224, groups of 10 micereceive an intraperitoneal injection of barbital (220 mg/kg).

It is found that, as from a dose of 2 mg/kg, CRL 41 224 reduces theduration of the sleep induced by barbital (total antagonism is obtainedat 32 mg/kg).

XII. ACTION ON THE "BEHAVIORAL DESPAIR"

Half an hour after they have received CRL 41 224, groups of 6 mice areplaced in a beaker filled with water to a height of 6 cm. The totalperiod of immobility between the 2nd and 6th minutes following immersionis noted.

It is observed that, at doses of 8 mg/kg and especially 32 mg/kg and 128mg/kg, CRL 41 224 reduces the period of immobility of mice which havebeen forcibly immersed.

XIII. CONCLUSIONS

The above neuropsychopharmacological tests as a whole show that CRL 41224 has

antidepressant effects: antagonism of the hypothermia induced byapomorphine, reserpine or oxotremorine, and reduction in the period ofimmobility or of "despair";

stimulant effects: excitation in mice, presence of stereotype movementsin mice and rats, potentiation of the stereotypies induced byapomorphine and amphetamine, increase in the motor activity, improvementin the motor recovery in mice whose motility has been depressedfollowing a brief period in a reduced-pressure enclosure, and distinctresumption in the motor activity of mice accustomed to their enclosure;and

peripheral α-adrenergic stimulant effects: mydriasis and antagonism ofthe ptosis induced by reserpine, and piloerection.

It follows that CRL 41 224 behaves as an antidepressant for the CNS. Theantidepressant effect is associated, at the same doses, with a distinctstimulant component.

B. TESTS RELATING TO CRL 41 219 (PRODUCT OF EXAMPLE 6)

The neuropsychopharmacological study of CRL 41 219 was carried out asindicated above for CRL 41 224. The results have been given below.

By intraperitoneal administration to male mice, the LD-30 (lethal dosefor 30% of the animals tested) is of the order of 128 mg/kg and theLD-50 is of the order of about 200 mg/kg.

Briefly, CRL 41 219 has a profile characterized by

stimulant effects:

in mice:

excitation with hyperreactivity,

hyperactivity, increase in the spontaneous motor activity, resumption inthe motor activity after habituation to the enclosure, improvement inthe motor recovery after hypoxic aggression, and increase in the numberof punished passes in the 4 plate test,

late appearance of stereotypies,

antigonism of the sleep induced by barbital;

in rats:

excitation (with hyperreactivity),

presence of stereotype movements and potentiation of the stereotypiesinduced by apomorphine and amphetamine;

antidepressant effects:

antagonism of the hypothermia induced by apomorphine, reserpine andoxotremorine,

reduction in the immobility of so-called "despair";

effects reflecting peripheral α-adrenergic stimulation:

antagonism of the ptosis induced by reserpine,

mydriasis,

antagonism of the trembling caused by oxotremorine.

Furthermore, CRL 41 219 seems to favor or potentiate the effects ofconvulsant agents (aggravation of the lethal effects of electric shock,reduction in the time taken for convulsions and death to occur followingasphyxiant anoxia).

These results as a whole show that CRL 41 219 is a substance possessingantidepressant, stimulant and arousing properties.

C. TESTS RELATING TO CRL 41 220 (PRODUCT OF EXAMPLE 7)

The neuropsychopharmacological study of CRL 41 220 was carried out inaccordance with the procedures given above for CRL 41 224.

I. TOXICITY

By intraperitoneal administration to male mice, CRL 41 220 has thefollowing LD-0, LD-30 and LD-50:

LD-0: greater than 128 mg/kg,

LD-30: of the order of about 250 mg/kg,

LD-50: of the order of about 500 mg/kg.

II. ACTION ON THE CNS

CRL 41 220 has antidepressant and stimulant effects.

III. CARDIOVASCULAR ACTION

Four dogs (average weight: 13.8 kg), anesthetized with nembutal, receiveCRL 41 220 by intraduodenal administration at successive doses of 0.1mg/kg, 0.5 mg/kg, 1 mg/kg, 2.5 mg/kg, 5 mg/kg and 10 mg/kg. The bloodpressure, the heart beat, the flow rate through the femoral artery, theflow rate through the vertebral artery and the rectal and/or skintemperature are measured and the coloration of the skin and the bile(collected by catheterization of the bile duct after ligature of thecystic duct) is observed.

It is found that, when administered intraduodenally, CRL 41 220

increases the vertebral flow rate as from a dose of 0.5 mg/kg, thefemoral flow rate at a dose of 1 mg/kg and the heart beat at a dose of2.5 mg/kg,

has a hypotensive effect at a dose of 10 mg/kg,

induces respiratory stimulation in the 4 dogs, and

increases the rectal and skin temperatures.

The effects of isoprenaline, tested after the intraduodenaladministration of CRL 41 220 at an accumulated dose of 19.1 mg/kg, arenot modified as regards the heart beat and are very slightly modified asregards the diastolic blood pressure: with 10 μg/kg of isoprenaline, thediastolic blood pressure changes from 112 mm Hg (i.e. about 1.49×10⁴ Pa)to 47 mm Hg (i.e. about 6.26×10³ Pa) instead of 158 mm Hg (i.e. about2.1×10⁴ Pa) in the control animals, and the heart beat changes from 221beats/minute to 275 beats/minute instead of from 175 beats/minute to 280beats/minute in the control animals (the dogs used for the tests alsobeing used as the control animals).

The hypertension induced by noradrenaline is reduced: with 2 μg/kg ofnoradrenaline, the systolic blood pressure changes from 202 mm Hg (i.e.about 2.69×10⁴ Pa) to 272 mm Hg (i.e. about 3.62×10⁴ Pa) after theintraduodenal administration of CRL 41 220, instead of from 199 mm Hg(i.e. about 2.65×10⁴ Pa) to 323 mm Hg (i.e. about 4.3×10⁴ Pa) in thecontrol animals.

Briefly, CRL 41 220 acts as a hypotensive agent (the hypotensive effectsresulting from the reduction in the diastolic blood pressure). As theinjection of 1 mg/kg of propanolol at the end of the test suppresses allthe effects of CRL 41 220, it is assumed that this product acts on thecardiovascular system by stimulating the β-adrenergic receptors.

IV. IMMUNOLOGICAL PROPERTIES

The test for cells forming lysis areas according to the technique of A.J. CUMMINGHAM et al. ("Further improvements in the plaque technique fordetecting single antibody forming cells"), Immunology 14, pages 599-601(1968), and measurement of the intensity of the delayed hypersensitivityto the red blood corpuscles of sheep according to the technique of T. E.MILLER et al. ("Immunopotentiation with BCG II modulation of theresponse to sheep blood cells"), Journal of the National CancerInstitute 51, (No. 5), pages 1669-1676 (1973), have made it possible todemonstrate the immunomodulating stimulant capacity of CRL 41 220.

V. COMPLEMENTARY TESTS

CRL 41 220 was shown to be active in the study of LEWIS' carcinoma inmice, according to the following protocol:

a. animals: consanguineous female mice (C₅₇ BL₆),

b. infecting cells: 10⁵ cells injected subcutaneously into the back ofthe animals,

c. monitoring of the tumor growth by measurement of the tumor twice aweek,

d. evaluation of the pulmonary metastases after fixation of the lungs ofthe dead animals in BOUIN's fixative.

Under these operating conditions, CRL 41 220 used by itself appears tobe inactive, whereas, on the one hand, cyclophosphamide (referenceanticancer agent), at a dose of 100 mg/kg, reduces the number ofplumonary metastases and slightly slows down the development of tumorswithout however improving the survival of the animals treated, and onthe other hand, at a dose of 150 mg/kg, it distinctly opposes theprocess initiated by the administration of infecting cells (survival of2 out of 6 animals).

Using the same procedures, the association of CRL 41 220 with 150 mg/kgof cyclophosphamide gives the results collated in Table II below.

                  TABLE II                                                        ______________________________________                                        association                                                                   cyclophosphamide                                                                          CRL 41 220 results                                                ______________________________________                                        150 mg/kg   100    mg/kg   increase in the toxicity                                                      compared with cyclo-                                                          phosphamide used by                                                           itself                                             150 mg/kg   5      mg/kg   substantially few                                                             differences compared                                                          with cyclophosphamide                                                         used by itself                                     150 mg/kg   2      mg/kg   unquestionable protective                                                     action in respect of                                                          LEWIS' carcinoma, all the                                                     animals treated still                                                         being alive several weeks                                                     after the experiment                               ______________________________________                                    

VI. CLINICAL TRIALS

CRL 41 220, administered orally to man at a dose of 250 to 500 mg (pergelatine capsule or tablet) gave good results in the treatment ofpatients presenting with circulatory disorders and having aninsufficient immunoreaction, for example in cases of recurrent herpes,rheumatoid polyarthritis and severe forms of measles.

D. TESTS RELATING TO CRL 41 232 (PRODUCT OF EXAMPLE 9)

The neuropsychopharmacological study of CRL 41 232 was carried outaccording to the procedures given above for CRL 41 224.

I. TOXICITY

When administered intraperitoneally to male mice, CRL 41 232 has

an LD-0 greater than 128 mg/kg and

an LD-30 of the order of about 250 mg/kg.

II. ACTION ON THE CNS

Briefly, CRL 41 232 has

antidepressant effects: antagonism of the hypothermia induced byapomorphine, reserpine and oxotremorine, and reduction in the period ofimmobility or "despair";

stimulant effects: excitation in mice, presence of stereotype movementsin mice and rats, potentiation of the stereotypies induced byapomorphine and amphetamine, increase in the motor activity, improvementin the motor recovery in mice whose motility has been depressedfollowing a brief period in a reduced-pressure enclosure, and distinctresumption in the motor activity of mice accustomed to their enclosure;and

peripheral α-adrenergic stimulation: mydriasis, exophthalmos andantagonism of the ptosis induced by reserpine.

CRL 41 232 behaves overall as a stimulant and antidepressant for theCNS.

E. TESTS RELATING TO CRL 41 236 (PRODUCT OF EXAMPLE 10)

The neuropsychopharmacological study of CRL 41 236 was carried outaccording to the procedures given above for CRL 41 224.

I. TOXICITY

When administered intraperitoneally to male mice, CRL 41 236 has

an LD-0 greater than 256 mg/kg and

an LD-30 of the order of about 500 mg/kg.

II. ACTION ON THE CNS

Briefly, CRL 41 236 possesses

antidepressant effects: antagonism of the hypothermia induced byapomorphine, reserpine and oxotremorine, and reduction in the immobilityor "despair";

stimulant effects: excitation with hyperreactivity, without the presenceof stereotype movements, hyperactivity (increase in the spontaneousmotility and in the motor activity after habituation to the enclosure),improvement in the motor recovery after hypoxic aggression, moderateincrease in the number of punished passes in the 4 plate test,potentiation of the stereotypies induced by apomorphine and amphetamine,and antagonism of the sleep induced by barbital;

peripheral α-adrenergic stimulation: antagonism of the ptosis induced byreserpine, and mydriasis.

Furthermore, CRL 41 236 seems to aggravate the lethal effects ofelectric shock.

Consequently, CRL 41 236 behaves as an antidepressant having stimulantand arousing properties.

F. TESTS RELATING TO CRL 41 240 (PRODUCT OF EXAMPLE 11)

Following the procedures described above for the study of CRL 41 224,the following properties were observed.

I. TOXICITY

When administered intraperitoneally to male mice, CRL 41 240 has an LD-0greater than 250 mg/kg.

II. ACTION ON THE CNS

Briefly, CRL 41 240 possesses

antidepressant effects: antagonism of the hypothermia induced byapomorphine, reserpine and oxotremorine, and reduction in the period ofimmobility or "despair" (this reduction perhaps being related to thestimulant component);

stimulant and arousing effects: excitation in mice and rats with thepresence of stereotype movements and potentiation of the stereotypiesinduced by apomorphine and amphetamine, increase in the motor activity,improvement in the motor recovery in mice whose motility has beendepressed following a brief period in a reduced-pressure enclosure,resumption in the activity of mice accustomed to their enclosure, andvery distinct antagonism of the sleep induced by barbital;

peripheral α-adrenergic stimulation: mydriasis, exophthalmos andantagonism of the ptosis induced by reserpine; and

anticonvulsant effects at a high dose: antagonism of the convulsanteffects of electric shock and increase in the time taken for asphyxiantconvulsions to occur.

It follows that CRL 41 240 behaves as an antidepressant and stimulantfor the CNS.

G. TESTS RELATING TO CRL 41 242 (PRODUCT OF EXAMPLE 12)

The neuropsychopharmacological study of CRL 41 242 was carried outaccording to the procedures described above for CRL 41 224, except thatthe pH of the aqueous solution of CRL 41 242 to be injectedintraperitoneally varies as a function of the concentration in themanner indicated in Table III below.

                  TABLE III                                                       ______________________________________                                        pH OF THE AQUEOUS SOLUTION TO BE INJECTED, AS                                 A FUNCTION OF THE CONCENTRATION OF CRL 41 242.                                       Concentration                                                                 of CRL 41 242                                                                           pH                                                           ______________________________________                                               50    g/liter 2.5                                                             13    g/liter 3.0                                                             2     g/liter 3.5                                                             0.8   g/liter 4.0                                                             0.4   g/liter 4.5                                                             0.2   g/liter 5.0                                                             ≦0.05                                                                        g/liter 5.5                                                      ______________________________________                                    

I. TOXICITY

When administered intraperitoneally to male mice, CRL 42 242 has an LD-0greater than 256 mg/kg and an LD-60 of the order of about 500 mg/kg.

II. ACTION ON THE CNS

Briefly, CRL 41 242, at high doses, has

sedative effects manifested by:

sedation in mice and rats with a decrease in the reactivities andhypothermia in mice,

a decrease in the spontaneous motility and the number of punished passesin the four plate test on mice,

a reduction in the intergroup aggression in mice,

an increase in the duration of the sleep induced by barbital in mice,

an increase in the time taken for convulsions and death to occurfollowing asphyxiant anoxia; and

antidepressant effects manifested by:

very moderate antagonism of the hypothermia induced by oxotremorine, and

a slight reduction in the period of immobility of mice which have beenforcibly immersed.

CRL 41 242 also has very discreet effects of the stimulant type at weakdoses.

III. IMMUNOLOGICAL PROPERTIES

CRL 41 242 was shown to be particularly valuable as an immunostimulantsubstance.

H. TESTS RELATING TO CRL 41 245 (PRODUCT OF EXAMPLE 13)

The neuropsychopharmacological study of CRL 41 245 was carried outaccording to the procedures described above for CRL 41 224.

I. TOXICITY

When administered intraperitoneally to male mice, CRL 41 245 has an LD-0greater than 256 mg/kg and an LD-100 less than or equal to about 512mg/kg.

II. ACTION ON THE CNS

Briefly, under experimental conditions, CRL 41 245 has

antidepressant effects:

antagonism of the hypothermia induced by apomorphine, reserpine andoxotremorine,

reduction in the period of immobility of mice which have been forciblyimmersed (perhaps associated with a stimulant component);

stimulant and arousing effects:

excitation with hyperreactivity in mice and rats,

increase in the spontaneous motor activity of mice with resumption inthe motor activity of mice accustomed to their enclosure, andimprovement in the motor recovery in mice subjected to acute hypoxia,

increase in the number of punished passes in the 4 plate test on mice,

reduction in the duration of the sleep induced by barbital,

presence of stereotype movements in mice and rats and potentiation ofthe stereotypies induced by apomorphine and amphetamine in rats; and

peripheral α-adrenergic stimulation:

piloerection in mice and rats,

mydriasis in rats,

reduction in the ptosis induced by reserpine in mice.

Furthermore, CRL 41 245 shows

total antagonism, at a strong dose, of the convulsant effects ofelectric shock,

a reduction, at a strong dose, in the intensity of the trembling due tooxotremorine, and

a reduction in the intergroup aggression.

In conclusion, CRL 41 245 behaves as an antidepressant with a strongstimulant component.

I. TESTS RELATING TO CRL 41 254 (PRODUCT OF EXAMPLE 15)

The neuropsychopharmacological study of CRL 41 254 was carried outaccording to the procedures described above for CRL 41 224.

I. TOXICITY

When administered intraperitoneally to male mice, CRL 41 254 has an LD-0greater than 256 mg/kg and an LD-100 less than or equal to 512 mg/kg.

II. ACTION ON THE CNS

At strong doses, CRL 41 254 has modest antidepressant effects(antagonism of the hypothermia induced by apomorphine andoxotremorine--but no antagonism of the hypothermia induced by reserpine)and weak stimulant effects (firstly a reduction in the duration of thesleep induced by barbital, and secondly a moderate resumption in themotor activity of mice accustomed to their enclosure).

III. IMMUNOLOGICAL PROPERTIES

At a dose of 1 mg/kg, CRL 41 254 has a statistically significantimmunostimulant activity according to the test for cells forming lysisareas after immunization by means of red blood corpuscles of sheet("PFCIgM" test), described by A. J. CUNNINGHAM et al., Immunology 14,pages 599-601 (1968), as mentioned above, and at doses of 10 to 100mg/kg administered orally, it has a statistically significantimmunostimulant activity according to the measurement of the intensityof the delayed hypersensitivity to red blood corpuscles of sheep,described by T. E. MILLER et al., Journal of the National CancerInstitute, 51 (No. 5), pages 1669-1676 (1973), as mentioned above.

J. TESTS RELATING TO CRL 41 262 (PRODUCT OF EXAMPLE 17)

CRL 41 262 has antidepressant and stimulant effects on the CNS. It wasshown to be particularly valuable as an immunomodulator because of itsimmunostimulant activity at doses of 0.1 mg/kg, 10 mg/kg and 100 mg/kgaccording to the abovementioned PFCIgM test, and at doses of 10 and 100mg/kg, administered orally, according to the abovementioned measurementof the intensity of the delayed hypersensitivity to red blood corpusclesof sheep.

K. TESTS RELATING TO CRL 41 247 (PRODUCT OF EXAMPLE 14)

The neuropsychopharmacological study of CRL 41 247 was carried outaccording to the procedures described above for CRL 41 224, the CRL 41247 to be tested being in solution in distilled water at pH 4.5-5.5.

I. TOXICITY

When administered intraperitoneally to male mice, CRL 41 247 has an LD-0greater than 512 mg/kg and an LD-60 of the order of about 1000 mg/kg.

II. ACTION ON THE CNS

Briefly, at strong doses only, CRL 41 247 has discreet antidepressanteffects manifested by very moderate antagonism of the hypothermiainduced by apomorphine and oxotremorine (but no antagonism towards thehypothermia induced by reserpine) and by a reduction in the period ofimmobility of mice which have been forcibly immersed; and stimulanteffects manifested by an increase in the motor activity of mice afterhabituation to their enclosure and after acute hypoxia.

It is also observed that, at strong doses, CRL 41 247 produceshypothermia (of -3.3° C., 30 minutes after the intraperitonealadministration of 256 mg/kg of CRL 41 247), a reduction in theconvulsant effects of electric shock and potentiation of thestereotypies induced by amphetamine.

III. IMMUNOLOGICAL PROPERTIES

It is observed that CRL 41 247 stimulates cell activity according to theabovementioned technique of T. E. MILLER et al.

L. TESTS RELATING TO THE PRODUCTS OF EXAMPLES 1-5

When administered intraperitoneally, CRL 41 152 (Example 1), CRL 41 177(Example 2), CRL 41 192 (Example 3), CRL 41 212 (Example 4) and CRL 41217 (Example 5), according to the invention, all have

(i) stimulant effects which appear especially as

excitation with hyperreactivity in mice,

an increase in the spontaneous motility in mice,

a resumption in the motor activity of mice accustomed to theirenclosure,

an improvement in the motor recovery in mice after acute hypoxia,

stereotype movements in rats,

antagonism of the sleep induced by barbital, and

potentiation of the stereotypies induced by apomorphine or amphetamine;(ii) antidepressant effects which appear especially as:

antagonism of the hypothermia induced by apomorphine, oxotremorine orreserpine, and

a reduction in the immobility or so-called "despair"; (iii) effectswhich may reflect peripheral adrenergic stimulation (especiallymydriasis, antagonism of the ptosis induced by reserpine and antagonismof the trembling caused by oxotremorine), whereas other signs ofα-adrenergic stimulation, such as salivation and exophthalmos, areabsent.

CRL 41 152, CRL 41 177, CRL 41 192, CRL 41 212 and CRL 41 217 all differfrom the amphetamines by the fact that the stereotype movements whichthey induce in rats are not suppressed by the prior injection ofalpha-methyl-tyrosine (which is a reference substance blocking thecatecholamine synthesis, this circumstance preventing the appearance ofthe stereotypies induced by amphetamine).

Furthermore, it is noted that, in contrast to CRL 41 192 andamphetamines, CRL 41 152, CRL 41 177, CRL 41 212 and CRL 41 217 do notincrease the toxicity to grouped mice compared with isolated mice.

Finally, CRL 41 152, CRL 41 192 and CRL 41 212 have anticonvulsanteffects towards the convulsions caused especially by electric shock,whereas CRL 41 177 and CRL 41 217 potentiate the convulsant effects ofelectric shock.

Moreover, when CRL 41 177 is administered gastrically to male mice (insolution in distilled water in a volume of 20 ml/kg), it is found that(i) its effect on spontaneous motilith and (ii) its interaction withbarbital are greater than on intraperitoneal administration.

M. SUPPLEMENTAL TESTS RELATING TO CRL 41 152 (PRODUCT OF EXAMPLE 1)

Further tests were carried out in order to point out the mechanism ofaction of CRL 41 152 in the organism. In these tests that product insolution in distilled water was administered in a volume of 20 ml/kg tomale mice and of 5 ml/kg to male rats per I.P. route.

a. Action on stereotypies in rats

Since (i) 41 152 administered per I.P. route to rats induces stereotypemovements, and (ii) α-methyltyrosine, a substance of reference which isknown to inhibit the synthesis of catecholamines in situ and to preventalmost totally the appearance of the stereotypies induced by amphetamineand amphetamine-like compounds, causes a slight inhibition of thesterotypies induced by CRL 41 152 (128 mg/kg of α-methyltyrosineadministered per I.P. route 2.5 hours before administration per I.P.route of 30 mg/kg of CRL 41 152, cause an inhibition of 4% of the CRL 41152 induced stereotypies), further assays were performed againsthaloperidol, reserpine and reserpine together with α-methyltyrosine.

Interaction with haloperidol

Batches of rats were administered per I.P. route with haloperidol 0,5hour before the I.P. injection of CRL 41 152 or amphetamine. Haloperidolat the dose of 0.25 mg/kg, almost totally prevents the appearance ofstereotypies induced by CRL 41 152 and amphetamine, and, at the dose of0.5 mg/kg totally inhibits the said stereotypies.

Interaction with reserpine

Batches of 6 male rats each were administered per I.P. route with 4mg/kg of reserpine either 4 hours or 24 hours before administration ofCRL 41 152 or methylphenidate. Reserpine administered 4 hours before CRL41 152 or methylphenidate totally prevents the appearance of thestereotype movements induced by CRL 41 152 and methylphenidate.Reserpine administered 24 hours before CRL 41 152 or methylphenidatecauses only a moderate reduction of the stereotypies induced by CRL 41152 and methylphenidate.

Interaction with reserpine and α-methyltyrosine

Batches of 6 rats each were administered with 4 mg/kg I.P. of reserpine(at T-24 h), with 128 mg/kg I.P. of α-methyltyrosine (at T-2,5 h) thenwith CRL 41 152 or methylphenidate (at T=0). They were immediatelyplaced into transparent enclosures for counting the stereotype movementsthat are normally induced by said CRL 41 152 and methylphenidate. It wasobserved that such an association of reserpine and α-methyltyrosinealmost totally prevents the appearance of the stereotype movementsprovoked by CRL 41 152 and methylphenidate.

Comments

According to the results of these assays it seems that:

(i) in view of the results of the interaction with haloperidol test, theCRL 41 152-induced stereotype movements would surely involve thestimulation of a post-synaptic dopaminergic receptor,

(ii) in view of the results of the tests of interaction with reserpineand with the reserpine/α-methyltyrosine association, CRL 41 152 wouldnot exhibit a direct action on the post-synaptic dopaminergic receptor,

(iii) consequently, CRL 41 152 would undirectly act on the post-synapticdopaminergic system. To be precise CRL 41 152 should involve

1. The liberation of newly synthetized dopamine (as illustrated by thenon-complete inhibition by α-methyltyrosine of stereotype movementsinduced by CRL 41 152), and

2. The participation of the dopamine issued from a pool comprising thenewly synthetized catecholamines, as the result of the inhibition of thedopamine recapture mechanism.

b. Influence of catecholamines on hyperactivity

A further series of assays was carried out on mice according to theteaching of S. L. HANDLEY et al. "Influences of catecholamines ondexamphetamine, induced changes in locomotor activity",Psychopharmacology 58, 283-288 (1978), in order to observe a potentialinfluence of dopamine or moradrenaline on the hyperactivity induced byCRL 41 152.

After a habituation period of 1.5 h to the actimeters, male mice(grouped into batches of 10 animals each and a control batch of 20animals) were administered (under slight anesthesia with ether) perintraventriculocerebral injection (i.e. I.V.C. route) with (i) either 10μg of noradrenaline, or 10 μg of dopamine or 10 μl (0.5 μl/second) ofsaline solution, then (ii) 5 minutes later, with CRL 41 152 (in solutionin distilled water) per I.P. route in a volume of 20 ml/kg, immediatelybefore replacing the mice in the actimeters wherein their motility wasrecorded for 1 hour by measuring the number of crossed rays per periodof 5 minutes). Batches receiving CRL 41 152 per I.P. route withnoradrenaline or dopamine per I.V.C. route were compared with (i) thecontrol batch receiving the saline solution per I.V.C. route thendistilled water per I.P. route, and (ii) batches receiving onlynoradrenaline, dopamine (per I.V.C. route) or CRL 41 152 (per I.P.route). At the dose of 8 mg/kg, CRL 41 152 induced a distinctstatistically significant increase in motor activity which appearedafter injection and continued during the one-hour recording.

The I.V.C. administration of 10 μg of noradrealine a 10 μg of dopaminedid not cause any visible locomotor effect by comparison with the I.V.C.administration of the saline solution.

The prior I.V.C. administration of noradrenaline induced a distinctstatistically significant decrease in the motor stimulant effect causedby CRL 41 152.

Unlike noradrenaline, the prior I.V.C. administration of dopamine didnot modify the motor caused by CRL 41 152.

These results clearly show that CRL 41 152 is differing from referencecompounds known as stimulant agents (such as amphetamine,methylphenidate, nomifensine, cocaine) the motor effects of which arepotentialized by I.V.C. administration of noradrenaline.

The favourable decrease in CRL 41 152 hypermotibility caused by theI.V.C. administration of noradrenaline cannot be explained by theApplicant in the light of his present knowlegde.

(c) Interaction with proadifen

Proadifen is a reference compound (coded as SKF 525-A) which inhibitshepatic microsomial enzymes and accordingly induces hypomotility inmice, and does not oppose the hypothermic effect of apomorpholine.

Two series of experiments were carried out. In the first one, male mice(12 per dose, 12 control animals) were administered per I.P. route (i)with proadifen (75 mg/kg) at T-3 h, then (ii) with CRL 41 152 at T-0,5h. At T=0 the mice were placed in actimeters, where their motility wasrecoded for 0.5 h. In the second one male mice (12 per dose, 12 controlanimals) were administered with proadifen and CRL 41 152 as indicatedhereinabove, then subcutaneously with apomorphine (16 mg/kg) at T=0 inorder to appreciate the potential variation of the hypothermia inducedby apomorphine.

In these two series CRL 41 152, in solution in distilled water, wasadministered per I.P. route to male mice in a volume of 20 ml/kg.

motility

CRL 41 152 administered alone increases the spontaneous motility inmice. This effect increases with the doses.

Proadifen administered alone induced hypomotility.

The administration of proadifen then CRL 41 152 does not cause adistinct reduction of the hypermotility which is induced by CRL 41 152.

This mainly suggests that the CRL 41 152 hypermotility does not arisefrom its transformation into an active metabolite (the alternatepossibility that there is a transformation of said CRL 41 152, whichfollows an enzymatic metabolite route that is not affected by proadifen,should be discarded according to the opinion of the Applicant).

Temperature variations

CRL 41 152 exhibits at a dose of 8 mg/kg and especially at a dose of 32mg/kg an antagonism vis-a-vis the hypothermia induced by apomorphine.

Proadifen exhibits, when used alone, an important hypothermic effect,but it does not modify the hypothermia by apomorphine.

In the other hand proadifen does block the antagonism exhibited by CRL41 152 vis-a-vis the hypothermic effect of apomorphine.

Neither proadifen, nor CRL 41 152, nor their combination modify therighting behaviour (i.e. =verticalization") and stereotypies induced byapomorphine.

This suggests that the antagonism of the CRL 41 152, which is exhibitedagainst the apomorpholine-induced hypothermia, seems to arise from thetransformation of said CRL 41 152 into an active metabolite.

In short, with respect to hypermotility, CRL 41 152 seems mainly to actby itself, while with respect to apomorholine-induced hypothermia saidCRL 41 152 seems to act through a metabolite compound.

d. Interaction with barbital

The cinetic study of the interactions with barbital (administration pergastric route), clearly showed the interest of CRL 41 152 as awakeningagent in the treatment of hypersomnia and GELINEAU's disease.

(e) Teratogenic study

Assays carried out on White New Zealand gravid female rabbits showedthat CRL 41 152 does not exhibit any harmful teratogenic effect and canbe administered accordingly to expectant women without trouble duringpregnancy.

In clinical trials, CRL 41 152 was shown to be an excellent drug fortreating depressions in man as well as hypersomnia and GELINEAU'sdisease, in the form of tablets or gelatine capsules each containingfrom 5 mg to 75 mg of active principle, at a rate of 1 to 3 individualdoses per day, and CRL 41 177 was also shown to be an excellentantidepressant drug in the form of tablets or gelatine capsules eachcontaining 2 mg of active principle, at a rate of 2 to 3 tablets orgelatine capsules per day.

What is claimed is:
 1. A compound of the formula: ##STR18## wherein NR₁R₂ is pyrrolidino, morpholino, thiomorpholino, hexamethyleneimino,piperazino, 4-methylpiperazino, 4-(β-hydroxyethyl)piperazino,4-phenylpiperazino or 4-(p-chlorophenyl) piperazino, X is CH₃ CONH, andY and Z are independently hydrogen or halogen; or an addition saltthereof.
 2. The compound according to claim 1, wherein ##STR19## is4-acetylaminophenyl, 4-acetylamino-3-chlorophenyl,4-acetylamino-3,5-dichlorophenyl, 3-acetylaminophenyl or3-acetylamino-4-chlorophenyl.
 3. The compound according to claim 1 thatis 1-(4-acetylaminophenyl)-2-morpholinopropanone or a non-toxic additionsalt thereof.
 4. The compound according to claim 1 that is1-(3-acetylaminophenyl)-2-morpholinopropanone or a non-toxic additionsalt thereof.
 5. The compound according to claim 1 that is1-(4-acetylaminophenyl)-2-(4-methylpiperazino)propanone or a non-toxicaddition salt thereof.
 6. The compound according to claim 1 that is1-(4-acetylamino-3-chlorophenyl)-2-pyrrolidinopropanone or a non-toxicaddition salt thereof.
 7. The compound according to claim 1 that is1-(3-acetylaminophenyl)-2-thiomorpholinopropanone or a non-toxicaddition salt thereof.
 8. The compound according to claim 1 that is1-(4-acetylaminophenyl)-2-thiomorpholinopropanone or a non-toxicaddition salt thereof.
 9. A central nervous system antidepressantcomposition comprising an effective amount of at least one compoundaccording to claim 1, or a non-toxic addition salt thereof, and aphysiologically acceptable excipient.